Stachel Shawn J, Coburn Craig A, Rush Diane, Jones Kristen L G, Zhu Hong, Rajapakse Hemaka, Graham Samuel L, Simon Adam, Katharine Holloway M, Allison Tim J, Munshi Sanjeev K, Espeseth Amy S, Zuck Paul, Colussi Dennis, Wolfe Abigail, Pietrak Beth L, Lai Ming-Tain, Vacca Joseph P
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co, West Point, PA 19486, USA.
Bioorg Med Chem Lett. 2009 Jun 1;19(11):2977-80. doi: 10.1016/j.bmcl.2009.04.033. Epub 2009 Apr 18.
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.
我们开发了一系列新型杂芳基β-分泌酶1（BACE-1）抑制剂。这些抑制剂以独特的方式与该酶相互作用，从而能以非传统模式实现强效结合。除了阐明它们的结合模式外，由于这些抑制剂的固有pKa以及BACE-1酶结合测定的pH值，我们还发现了一种对结合亲和力的pH依赖性效应。
